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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Regulation of chromatin remodeling and gene activity by A-kinase anchoring proteins

Tildelt: kr 4,5 mill.

The nuclear matrix is essential for controlling gene expression in eukaryotic nuclei by organizing chromatin and orchestrating nuclear processes such as replication and transcription. AKAP95 is the major PKA and PP1-binding A-kinase anchoring protein (AKA P) of the nucleus; yet its function in interphase is unknown. AKAPs can bind multiple molecules and are regarded as anchoring platforms integrating multiple signaling pathways essential for cell communication, motility, proliferation and differentiation. Reports suggest a role of AKAP95 in the regulation of chromatin function. Notably, AKAP95 is a nuclear matrix and DNA-binding Zn-finger protein that binds transcriptional coactivators and chromatin remodelers. We hypothesize that several nuclear processes are regulated via tethering of signaling molecules to chromatin by AKAP95. We will therefore characterize the genomic regions occupied by AKAP95 and address the role of AKAP95 in regulating chromatin organization, with implications on gene activity and c ell fate. HYPOTHESIS 1 postulates that AKAP95 occupies genomic sites, some of which are co-enriched in chromatin remodeling factors identified as AKAP95 interactors. We will map on a genome scale occupancy sites of AKAP95, the epigenetic landscape around AKAP95, and occupancy of AKAP95 binding factors implicated in chromatin modeling. HYPOTHESIS 2 postulates that AKAP95 has a targeting role for chromatin effectors to the genome and a regulatory role in chromatin remodeling activities by the targeting fact ors. We will test the AKAP95-dependency of targeting of AKAP95 interactors with a role in chromatin function. The function of these factors will be assessed after AKAP95 depletion.


FRIMEDBIO-Fri prosj.st. med.,helse,biol